Clinical Considerations in Major Depressive Disorder: Focus on Treatment-Resistant Depression
CME/CE Released: 05/12/2009; Valid for credit through 05/12/2010
Patient History
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A 38-year-old mother presents to her primary care provider (PCP) with decreased energy/fatigue, feelings of hopelessness, irritability, difficulty concentrating, and persistent feelings of "emptiness." She had initially attributed these symptoms to managing with 3 sons who were younger than 6 years old, but reported that the symptoms continued to worsen over the past 3 weeks. Results from her laboratory assessments ruled out hypothyroid disease and other potential medical causes of these symptoms. In her follow-up visit, the PCP obtains additional medical and symptomatic information and diagnoses her as having new-onset nonpsychotic major depressive disorder (MDD). Her PCP prescribes the selective serotonin reuptake inhibitor (SSRI) fluoxetine (20 mg/day), increasing the dose to 40 mg/day after 4 weeks. After 8 weeks, she still has not demonstrated any response to the medication.
Approximately what percentage of patients with MDD fails to demonstrate an adequate clinical response to their first-line antidepressant therapy?
| Your Colleagues Responded: | |||
| 10% to 20% |  8% |
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| 20% to 30% | 33% |
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| 30% to 50% | Correct Answer | 43% |
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| 40% to 60% | 14% |
MDD affects approximately 10% of American adults, or an estimated 21 million people, each year.[1] Nearly 10% of all primary care office visits are for depression, and primary care clinicians provide nearly half the outpatient care for depressed patients.[2,3] With a lifetime prevalence of 16.6%,[4] the consequences of MDD can be severe, including impairments to the patient's physical and psychological well-being, quality of life, and daily living activities. The social and economic consequences are staggering -- MDD is the leading cause of disability worldwide.[5]
The etiology of MDD is multifactorial, involving both genetic and environmental influences, and is believed to involve the dopamine, norepinephrine, and serotonin transmitter systems. The goal of antidepressant treatment is remission, which is typically defined as "complete relief from the depressive episode."[6] Until recently, response, which indicates substantial symptomatic improvement, was considered a sufficient goal; however, research demonstrates that remission is associated with a better prognosis, lower likelihood of relapse, and better daily functioning than response.[7,8] Response without remission has been associated with a substantially greater number of somatic symptoms vs remission, including impairments in social functioning.[9] In fact, the current American Psychiatric Association and Agency for Healthcare Research and Quality (originally Association for Health Care Policy and Research) guidelines both identify remission as the goal of treatment.[7,10,11]
MDD treatment is typically conceptualized as having 3 phases: (1) the acute treatment phase, whereby remission is ideally induced (approximately 3-4 months); (2) the continuation phase, in which remission is preserved (4-9 months); and (3) the maintenance phase. A majority of patients will require pharmacologic intervention during the first 2 phases. Susceptible patients -- including those who have had at least 2 depressive episodes -- may require pharmacologic and/or nonpharmacologic interventions against a recurrence of another MDD episode throughout the maintenance phase, which for some can be lifelong. Typically, the initial treatment option for MDD is an SSRI or selective norepinephrine reuptake inhibitor (SNRI) (Table 1).[12] Other common initial treatments include tricyclic or tetracyclic antidepressants, serotonin modulators, norepinephrine serotonin modulators, and monoamine oxidase inhibitors (MAOIs). There are no true meaningful clinical differences between the psychotropic medications for MDD, although there are substantial differences in tolerability.[13-15] Agent selection may depend on the patient's prior response (if any) to these agents, anticipated side effects, safety, tolerability, and cost of the agent. MAOIs are generally limited to nonresponsive patients because of the risk for serious side effects and the required dietary restrictions.
Table 1. Pharmacologic Treatment Options for Major Depressive Disorder
| Selective Serotonin Reuptake Inhibitors |
|---|
| Citalopram (Celexa®) |
| Escitalopram (Lexapro®) |
| Fluoxetine (Prozac®) |
| Fluvoxamine (Luvox®) |
| Paroxetine (Paxil®) |
| Sertraline (Zoloft®) |
| Selective Norepinephrine Reuptake Inhibitors |
| Mirtazapine (Remeron®) |
| Venlafaxine (Effexor®) |
| Selective Serotonin Norepinephrine Reuptake Inhibitor |
| Duloxetine (Cymbalta®) |
| Other |
| Bupropion (buproprion, Wellbutrin®) |
| Nefazodone hydrochloride |
| Trazodone (Desyrel®) |
It is estimated that 30% to 50% of patients fail to show a significant response to their first adequate course of treatment, regardless of the class of agent
prescribed.[7,12,16] Across all efficacy trials, 54% of patients treated with second-generation antidepressant agents
for acute phase MDD failed to achieve remission, and 38% failed to achieve a response.[13] Nevertheless, results from
the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial suggest that approximately two thirds of patients may ultimately reach remission; however, this may require up to 4
treatment attempts.[17] Thus, clinicians need to reassure their patients that it is not uncommon for initial
interventions to result in less-than-desired responses, but with additional therapy remission is possible if not probable.
After 8 weeks of treatment, the patient still has no response to a moderate dose of fluoxetine. Which is the most appropriate treatment choice now?
| Your Colleagues Responded: | |||
| Wait another 2-4 weeks before changing | 12% |
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| Switch to another SSRI | Correct Answer | 50% |
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| Augment the original SSRI with a second SSRI | 12% |
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| Augment the original SSRI with cognitive therapy | 24% |
- The patient has experienced a trial of adequate duration of a moderate dose of a sufficient duration with no apparent response. Results from STAR*D support switching the patient to another agent without waiting any longer for a possible response.
STAR*D compared algorithmic treatment effectiveness and tolerability using real world adult patients with nonpsychotic major depression (N = 4041, aged 18-75 years) obtained from both primary care and specialist practices.[18,19] STAR*D was supported by the National Institute of Mental Health and was conducted for 5 years. See Table 2 for the study progression. All patients were initially treated with the SSRI citalopram (Level 1).
Table 2. STAR*D Algorithm: Treatment Levels
| Level 1 | Citalopram (Celexa®) | |
| Level 2 | Patients could choose one of the following: | |
| SWITCH | AUGMENT | |
| Stop citalopram, be randomized to receive one of the following: Bupropion sustained-release (Wellbutrin SR®) Venlafaxine extended-release (Effexor XR®) Sertraline (Zoloft®) Cognitive therapy |
Keep citalopram, be randomized to also receive one of the following: Bupropion sustained-release Buspirone (BuSpar®) Cognitive therapy |
|
| Level 2a (only for those receiving cognitive therapy in Level 2) | SWITCH | |
| Stop cognitive therapy, be randomized to receive one of the following: Bupropion sustained-release OR Venlafaxine extended-release |
||
| Level 3 | Patients could choose one of the following: | |
| SWITCH | AUGMENT | |
| Stop current therapy, be randomized to receive one of the following: Mirtazapine (Remeron®) Nortriptyline (Pamelor®) |
Keep current therapy, be randomized to also receive one of the following: LithiumT3 thyroid hormone (Cytomel®) |
|
| Level 4 | SWITCH | |
| Stop current therapy, be randomized to receive one of the following: Tranylcypromine (Parnate®) Mirtazapine + Venlafaxine ER |
||
Adapted from Gaynes BN, Rush AJ, Trivedi MH, Wisniewski SR, Spencer D, Fava M. The STAR*D study: treating depression in the real world. Cleve Clin J Med. 2008;75:59
Remission was defined as a Hamilton Rating Scale for Depression (HAMD17) score = 7; response was defined as a reduction of at least 50% on the Quick Inventory of Depressive Symptomatology, Self-report. Twenty-eight percent of the patients achieved remission following the initial treatment with citalopram; switching or augmenting with another agent allowed another 17% to 30% of those patients to achieve remission; hence, 57% of patients achieved remission with 2 treatment steps. As patients required additional treatment steps, they had lower acute remission rates, greater degrees of treatment intolerance, and higher relapse rates. Twelve percent to 25% of patients who entered level 3 and only 7% to 14% of patients in level 4 achieved remission.[7]
STAR*D researchers found that although most patients who experienced remission with the initial medication did so by week 6, a substantial proportion of patients first remitted between weeks 6 through 12.[12,17] Consequently, clinicians are typically advised to wait at least 8 weeks before switching medications. This patient was adherent with her initial medication regimen, which involved a moderate dose of fluoxetine for 8 weeks. She experienced an adequate duration with no response, indicating that, based on results from STAR*D, she would best be served by switching to another agent. Of interest is that STAR*D researchers found no apparent benefit to switching between classes vs within class: The patient is equally likely to respond to a different SSRI as to an SNRI or SSRNI after failing 1 or more aggressive medication trials.[12,14,15,17] Other factors, such as side effect profile, availability of generics, cost, and tolerability, might be considered when making the selection.
The clinician switches the patient to sertraline (titrated to 150 mg/day after 4 weeks of treatment). She is tolerating the medication well and she reports a partial improvement after 6 weeks of treatment.
What are her treatment options now?
| Your Colleagues Responded: | |||
| Don't make any therapeutic changes just yet | Correct Answer | 62% |
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| Switch her to another SSRI | 6% |
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| Switch her to another class of agents | 8% |
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| Add another agent to the SSRI (augmentation) | 22% |
Before making any treatment changes, it is recommended that the clinician review the initial diagnosis to (1) rule out any comorbid medical or psychiatric conditions; and (2) to determine if this is a subtype of MDD, such as a psychotic depression or an atypical depression, that might require an alternative treatment approach. It is particularly important to consider the possibility of this episode being the depressed phase of a bipolar (vs unipolar) disorder. Other comorbidities to consider include substance use/abuse, anemia, sleep apnea, personality disorders, anxiety disorders, and vitamin deficiencies. Only 30% to 50% of patients who have depression are successfully identified and diagnosed with depression by their PCP.[20]
Research suggests that more than half of treatment nonresponse can be attributed to either poor treatment adherence and/or poor tolerability.[12] Before making any changes to a medication regimen, the clinician should first ensure that the patient took the prescribed medication consistently and correctly; that the recommended dose was at least a moderate level; and that the patient took the medication for a sufficient duration (typically considered to be at least 8 weeks). STAR*D results found that it may require longer durations to reach remission on antidepressant agents, suggesting that clinicians wait for at least 8 weeks before switching or augmenting the current therapy (providing the patient is on at least a moderately aggressive dose).[17,21]
There is the belief that primary care clinicians see patients presenting with less severe depression than those cases seen by psychiatrists. However, new research indicates little difference in depressive severity or psychiatric comorbidity between the 2 settings.[17] Although primary care providers may report discomfort regarding treating treatment-resistant depression (TRD) and are likely to refer patients out to specialists for continued pharmacologic management, results from STAR*D demonstrate that patients can achieve comparable remission and response rates in either a primary care or specialty care setting, as long as identical care has been provided.[22] Furthermore, remission rates suggest that 2 adequate antidepressant trials in primary care are reasonable before referral to psychiatric clinics.[17] However, in the real world setting, results from the National Comorbidity Survey Replication found that only 42% of depressed patients received adequate treatment. Substantially more patients with depression requiring treatment who were seen in specialty settings received adequate care than patients seen in primary care settings (64% vs 41%, respectively).[23] Furthermore, it is estimated that only 40% of patients in a primary care practice setting take adequate doses of antidepressants during the first 6 months of treatment[24] and 42% discontinued their medication within the first month.[25]
After another 4 weeks on this treatment regimen, the patient continues to report a partial response. The clinician re-evaluates the initial diagnosis to rule out bipolar disorder and other psychiatric comorbidities. The clinician discusses the treatment options with the patient and they choose to augment her current treatment with another antidepressant.
True or false: Based on the patient's symptoms to date, she has treatment-resistant depression.
| Your Colleagues Responded: | |||
| True | Correct Answer | 51% |
|
| False | 48% |
The definition of TRD is somewhat ambiguous but is typically considered by most clinicians to indicate an inadequate response to at least 2 trials of antidepressants of adequate dose (at least a moderate dose within the range for that agent) and sufficient duration (considered = 8 weeks).[25] While "inadequate response" is also defined in various ways, treatment guidelines and STAR*D data all support remission as the goal of treatment and, hence, an adequate response. There are at least 3 algorithms[25] for staging treatment resistance in depression. The original Thase-Rush TRD Staging Method,[27] which uses 5 stages/levels, defines TRD as failure of at least 1 adequate trial, and prioritizes the medications. The European Staging method[28] defines TRD as failure to respond to 2 adequate trials of different antidepressant agents prescribed in adequate doses for at least 6-8 weeks. Finally, the Massachusetts General Hospital Staging Method[29] assigns a score value to each trial failure and makes no assumptions about treatment hierarchies.
TRD is not limited to patients with severe depression; it can involve mild or moderate depression that causes reduced daily functioning. However, it is limited to patients with unipolar depression, and excludes patients with bipolar disorder and/or severe Axis I comorbidity.[12] TRD is associated with a worse prognosis vs that of remitted patients, as well as higher outpatient medical costs and twice the risk for medical or psychiatric hospitalization.[30]
In STAR*D, 60% to 70% of the MDD patients met the criteria for TRD.[7] Of note is that two-thirds of the STAR*D patients achieved remission after 4 treatment trials. Before diagnosing TRD, the clinician must first rule out pseudoresistance, defined as an inadequate or unsatisfactory response due to inadequate treatment (dose or duration). Patients might also experience depressive breakthroughs, described as a return of the depressive symptoms during continued antidepressant treatment.
Settings of Care
A number of treatment guidelines agree that patients with MDD can be treated successfully in primary care or psychiatry settings in the absence of suicidality or bipolarity, and/or until the patient has failed at least 1 treatment approach during the current episode.[22] Results from STAR*D support this, finding no statistically significant difference in outcome between primary care and specialist settings for patients with TRD at either level 1[22] or level 2.[14] Although PCPs in STAR*D saw their MDD patients a fewer number of visits than did specialists, the PCPs saw their patients earlier and were therefore able to diagnose them sooner.[22] Contrary to expectations, there were no substantial differences in MDD presentation in the 2 settings. In both settings, a greater baseline severity was associated with a lower likelihood of remission. While the PCPs prescribed generally lower doses of medications for their patients than did the specialists, these differences did not yield clinically meaningful differences.[22]
The STAR*D findings highlight the value of implementing a systematic approach to treatment and of using routine measurements of symptoms through easily administered tools. STAR*D also emphasized the value of involving both office staff and the patient in the provision of care. Depression severity indices are useful tools for this goal. In their recent study, Duffy and Chung found that systematic monitoring of depression severity via the Patient Health Questionnaire (PHQ-9) substantially influenced clinical decision making -- specifically leading to ≥ 1 treatment change (either increasing the dose or changing the medication) in 40% of their cases.[31]
As of yet, there are no clear predictors for nonadherence to antidepressant use throughout the longest phases of MDD treatment -- specifically during the continuation and maintenance phases.[32] The prevalence of nonadherence is extremely high -- nearly half of all patients (46.5%) are nonadherent over 2 years of therapy.[32] Involving the patient in her/his own care enhances the prognosis and minimizes the risk for attrition, which has been associated with a substantially decreased likelihood of attaining remission.[33]
Case 2
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A 75-year-old, recently widowed gentleman with no psychiatric history presents to his PCP with gradual onset of depressive symptoms. He is currently on atorvastatin for high cholesterol; low-dose aspirin to prevent heart attack; propranolol for hypertension; tamsulosin for benign prostatic hyperplasia; naproxen for arthritis; eszopiclone to help with his sleep problems; glyburide for diabetes mellitus; trazodone, which was prescribed but never removed even after eszopiclone was added; vitamin E and fish oil (for his eyes and gastrointestinal tract); and a multivitamin. He has no interest in seeing a psychiatrist -- he only wants to be treated by his PCP.
Which of the following options is not an appropriate initial therapeutic approach for this patient?
| Your Colleagues Responded: | |||
| Prescribe paroxetine | Correct Answer | 53% |
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| Evaluate his medication history and current medical needs | 13% |
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| Administer a depression screening instrument or perform a clinical interview for depression | 13% |
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| Refer him to a psychotherapist for grief counseling | 19% |
Comorbid medical and psychiatric illness is extremely common in patients with MDD. In the STAR*D trial, two thirds of patients had at least 1 other psychiatric disorder.[21] Such comorbidities can complicate both the diagnosis and treatment of the respective conditions. Medical and psychiatric comorbidity increases the risk for relapse.[14] However, there appears to be no difference with regard to remission rates or time to remission among older depressed patients who had earlier vs later onset of depression, and the majority of patients in STAR*D had earlier-onset (72%) vs late-onset (28%) depression.[34] Earlier age of onset has been associated with greater illness burden, including poorer quality of life, more lifetime depressive episodes, and greater social and occupational impairments.[35]
Before prescribing any additional medications for this patient, the clinician must first clearly determine whether the patient should be diagnosed with depression or if the depressive symptoms are associated with or caused by his numerous medications and medical conditions. Toward this end, the clinician administers the 15-item Geriatric Depression Screen (GDS) on which the patient scores an 8, suggestive of a depressive disorder.[36] A clinical interview confirms the suspicion of MDD.
Depression is a common comorbidity of type 2 diabetes,[37] but remains undiagnosed in 45% of patients with both conditions.[38] Research suggests that clinicians "expect" a patient with diabetes to experience distress, thereby minimizing its severity and under-diagnosing clinical depression.[39,40] However, the co-occurrence of diabetes with depression is associated with a significant increase in all-cause mortality.[41] In this particular case, the patient reports he has been consistently compliant with his diabetes regimen (for decades) and his diabetes remains medically under control.
The number and variety of medications this patient is taking necessitate taking a comprehensive medical history, with special attention to his medications. Many medications have side effects that confound and/or contribute to depression. It is possible that eliminating some of the medications, altering the dosages, or substituting comparable agents might eliminate the depressive symptomatology. In this case, the PCP immediately discontinued the prescription for eszopiclone but retained the prescription for trazodone, reasoning that only 1 sleep aid was necessary and long-term use of sedative-hypnotic agents has been associated with memory loss and cognitive impairments -- which can be of particular concern for the elderly.[42] In addition, the PCP decided to prescribe atenolol in place of propranolol for his hypertension, noting that propranolol might be more fatiguing than atenolol.[43] The PCP refrains from prescribing any other medication for the possible MDD until he has ruled out any contribution to the depression from the patient's medications.
The patient returns for his scheduled follow-up visit after 4 weeks, still complaining of depressive symptomatology.
Which of the following antidepressant agents carries an increased risk for drug-drug interactions?
| Your Colleagues Responded: | |||
| Sertraline | 14% |
||
| Citalopram | 11% |
||
| Paroxetine | Correct Answer | 43% |
|
| Venlafaxine | 30% |
All SSRIs are metabolized in the liver by the cytochrome P450 (CYP450) enzyme system -- primarily, the CYP2D6, CYP2C19, and CYP2C9 enzymes -- although to varying degrees.[44] Fluoxetine and paroxetine are potent inhibitors of CYP2D6; in contrast, citalopram, venlafaxine, and sertraline (at lower doses) are less potent and therefore less likely to interact with coadministered medications.[45,46] This is of paramount importance when selecting an appropriate antidepressant for a patient already on multiple medications.
Another consideration for medication selection involves the risk for serotonin syndrome, which has been described in a number of case reports and can occur as a result of dangerously high levels of serotonin -- possibly owing to taking SSRIs, SNRIs, or MAOIs along with other medications that affect serotonin levels (such as triptans for migraine, St. John's wort, or lithium), or even taking a single previously used serotonin-enhancing drug at an increased dose. Serotonin syndrome can result in fever, hallucinations, seizures, and even coma. This patient is currently receiving naproxen for pain and inflammation management of his arthritis, neither of which has been associated with an increased risk for serotonin syndrome.
The patient is initially given citalopram 10 mg/day. He is titrated to 20 mg/day after 2 weeks with no response, and eventually to 30 mg/day after 6 weeks. After 8 weeks on the medication, he reports no response and no symptomatic improvements.
What therapeutic approach do you recommend next?
| Your Colleagues Responded: | |||
| Increase the dose of citalopram to 40-50 mg/day | 12% |
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| Augment citalopram with another antidepressant | 8% |
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| Switch to another antidepressant | Correct Answer | 67% |
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| Wait another 2-4 weeks before making any changes | 11% |
- The patient has failed to respond to a moderate dose (for his age) of citalopram after 8 weeks of therapy. An appropriate option would be to switch to another agent instead of adding more medications to his already full regimen.
No one single antidepressant has been found to be more effective than any of the other agents.[47] Little is known regarding the dosing requirements for antidepressants of younger vs older patients with depression, although anecdotal evidence suggests that geriatric doses should be about half the usual adult dose. Early research recommended lower doses for tricyclic antidepressants and benzodiazepines among elderly patients than their younger cohorts to avoid side effects and the risk for drug interactions.[48] In addition, clinicians and patients should anticipate a longer onset of response time for these agents to afford symptomatic relief.[48] Of particular concern with geriatric pharmacology is the risk for severe adverse reactions and/or changes to mental status (leading to confusion, sedation, and/or cognitive impairments).[49]
The patient is switched to sertraline (100 mg/day) and reports a partial response at 8 weeks, but nausea prevents any further increase in his dose. He is ambivalent about taking another medication, and often talks about the loss of his wife.
Which of the following augmentation strategies would you now recommend?
| Your Colleagues Responded: | |||
| An atypical antipsychotic | 10% |
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| Electroconvulsive therapy | 3% |
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| Cognitive behavioral therapy | Correct Answer | 79% |
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| Nothing | 6% |
Cognitive behavioral therapy (CBTs) is a safe and effective approach to the treatment of depression, as a monotherapy or in combination with antidepressant medications. Recent studies have demonstrated the efficacy of this psychotherapeutic approach for depression and anxiety in adults.[50-52] Hanson and Scogin[52] found that older adults preferred CBT as a more acceptable treatment than antidepressant medication for the treatment of mild-to-moderate depression; in addition, CBT was preferred as either monotherapy or in combination with pharmacotherapy for severe depression. CBT may be a particularly appropriate therapeutic approach for this patient, who was still grieving the loss of his spouse.
The safety and efficacy of augmentation with an atypical antipsychotic agent among elderly patients was recently demonstrated in a 12-week, open-label pilot study involving 24 geriatric patients.[53] Older patients (≥ 65 years) with MDD who had had a partial response to either an SSRI or SNRI received adjunctive aripiprazole (2.5-15 mg/day) for 12 weeks. The therapy was tolerated well and led to significant improvements in the symptoms of depression. Additional research is warranted for this specific population, and for other atypical antipsychotic agents.
A unique and cost-effective augmentation strategy highlights the benefits of exercise in elderly patients. An epidemiologic study found that exercise (physical activity) is associated with reduced depression among a cohort of depressed adults.[54] In addition, physical activity was shown to be particularly helpful for patients with medical problems and other major life stressors.
Case 3
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A 47-year-old female with recurrent episodes of MDD presents to her new PCP with a recent history of documented failures of 2 courses of different SSRI
antidepressants. She reports that her prior physician had also diagnosed a comorbid anxiety disorder. She has been taking venlafaxine (225 mg/day), to which she has had a partial
response over the past 2 months.
What is the prevalence of anxiety symptoms in patients with MDD?
| Your Colleagues Responded: | |||
| 10%-25% | 3% |
||
| 25%-33% | 21% |
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| 33%-66% | Correct Answer | 59% |
|
| > 66% | 16% |
Depression and anxiety commonly co-occur. In the STAR*D trial, 44.6% of patients had symptoms of anxiety.[7] Depressed patients with comorbid anxiety disorder may be at elevated risk for suicide[55]; furthermore, patients with comorbid anxiety disorder and/or with substance use/abuse disorders have more social problems and worse pharmacologic outcomes.[56] Treatment for both anxiety and depressive disorders typically involve SSRIs as the initial therapy of choice,[57] although some SSRIs and SNRIs can temporarily increase symptoms of anxiety, including jitteriness, agitation, and insomnia.[55] Consequently, these patients require a more aggressive and multifaceted approach to treatment.[56] A recent prospective, community-based cohort study found that nearly 90% of patients with persistent depression and anxiety over a 3-year period failed to receive both appropriate medication and counseling.[58]
The clinician is concerned that increasing the patient's dose might lead to potential hypertensive side effects and decides instead to augment the treatment. Which of the following would be reasonable pharmacologic options?
| Your Colleagues Responded: | |||
| Lithium | 7% |
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| Buspirone | 46% |
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| L-triiodothyronine (T3) | 3% |
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| Any would be appropriate | Correct Answer | 27% |
|
| None of the above | 14% |
Augmentation therapy refers to the addition of drugs that may or may not be standard antidepressants to enhance the effect of a classical antidepressant agent.[16] The rationale is to cause a different neurochemical effect by affecting different neurotransmitter systems, and to broaden the therapeutic effect. In addition to the standard antidepressants, there is a wide range of agents that can be used for augmentation, including (but not limited to) lithium, triiodothyronine (T3), buspirone, pindolol, serotonin precursors, psychostimulants, atypical antipsychotics, benzodiazepines, and anticonvulsants. The selection process must consider the side effects of the augmenting agents -- such as effects on sleep, weight, metabolism, or anxiety. Combination therapies can involve combinations of medications, medication plus psychotherapy, or medication with nonpharmacologic therapies (Table 3).
Table 3. Augmentation/Combination Strategies
| +++ | ++ | + | +/(-) |
|---|---|---|---|
| Clear Efficacy | Some Efficacy | Suggested Efficacy | Anecdotal Efficacy |
| Atypical antipsychotics | Lithium | Dopaminergics | DHEA |
| Modafinil | Pindolol | Estrogens | |
| Buspirone | Riluzole | Testosterone | |
| T3 | SAMe/ | Opiates | |
| Psychostimulants | Methylfolate | ||
| Anticonvulsants | |||
| Benzodiazepines | |||
| Omega-3 |
From Fava M, Rush AJ. Psychother Psychosom. 2008;75:139
Historically, research on augmentation strategies has focused on combinations with tricyclic antidepressants; there is less research regarding combinations with SSRIs or SNRIs.[16]
Despite potential tolerability and cost concerns,[59] the atypical antipsychotic agents have shown efficacy as augmentation options. Aripiprazole[59-61] has been approved by the US Food and Drug Administration (FDA) as an adjunctive therapy for MDD; olanzapine[61] has been approved for use in TRD in combination with fluoxetine. The FDA in April found quetiapine to be safe and effective as adjunctive therapy for MDD, although this indication is not currently approved. Ziprasidone[62] and risperidone[63,64] appear to have at least limited efficacy, although additional investigations are warranted.
Lithium augmentation is a well-researched option; however, the risk for toxicity, need for blood monitoring, and low overall response rates associated with this approach limit its usefulness. Thyroid augmentation, preferably with L-triiodothyronine (T3) vs thyroxine (T4), has been shown in STAR*D to afford higher remission rates than lithium augmentation, although neither option affords superior remission rates.[65]
Modafinil, a wake-promoting agent, may be helpful for patients with a partial response to SSRIs and persistent fatigue or sleepiness and has been studied in a randomized, double-blind trial,[66] as have ropinirole[67,68] and buspirone, which was shown to be comparable to placebo for TRD[69] but more effective than placebo for patients with severe depression.[70]
Small, mostly open label studies have shown augmentation with dopaminergic agents (D2/D3 agonists), such as pergolide,[71,72] amantadine,[73] and pramipexole,[74] may be helpful. There is anecdotal evidence supporting the use of some of the anticonvulsants, including lamotrigine,[75,76] gabapentin,[77] topiramate,[78] carbamazepine,[79] and valpromide,[80] particularly for patients with anxiety concerns, although there may be tolerability issues regarding sedation and weight gain associated with many of these agents.
Among the other agents that have been or are currently being investigated for augmentation are extended-release methylphenidate, a stimulant approved for attention-deficit/hyperactivity disorder; S-adenosyl-L-methionine (SAM-e); benzodiazepines and hypnotics; opiates; hormones (dehydroepiandrosterone, testosterone, and estrogen); riluzole; inositol; and the omega-3 fatty acid ethyl-eicosapentaenoate. Additional research is indicated for these agents.
All but which of the following nonpharmacologic devices have been approved by the US FDA for the treatment of MDD?
| Your Colleagues Responded: | |||
| Electroconvulsive therapy (ECT) | 23% |
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| Magnetic seizure therapy (MST) | Correct Answer | 42% |
|
| Repeated transcranial magnetic stimulation (rTMS) | 12% |
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| Vagus nerve stimulation (VNS) | 21% |
The plethora of new, nonpharmacologic approaches to the treatment of TRD has focused on developing and expanding existing therapies that seek to restore normal brain activity through either electrical or magnetic stimulation. ECT has long been a therapeutic option for patients with depression -- particularly patients with acute suicidal ideation, delusions, or catatonia.[81] ECT is sometimes perceived as a treatment of last resort because of the potential for substantial cognitive side effects, including acute confusional state, anterograde amnesia, and the possibility of retrograde amnesia. Half of the patients undergoing ECT will have improvement within the first week, and nearly two thirds of patients will achieve remission after 10 treatments. However, at least 50% of those will relapse within the first year if there is no supportive pharmacologic prophylactic management.[81]
Over the years, investigators have developed similar approaches to ECT that might afford patients a quicker recovery with improved tolerability. Two recently approved nonpharmacologic approaches include rTMS and VNS. rTMS is noninvasive and more generally available to patients compared with MST, and involves the use of a magnetic field on the scalp surface to focus electric stimulation onto the brain cortex. It has been shown in studies to be comparable to ECT for the treatment of patients with nonpsychotic depression, but is inferior to ECT for patients with psychotic depression.[81] rTMS provides a better cognitive side effect profile compared with ECT, as it does not induce grand mal seizures or transient memory loss. Vanderhasselt and colleagues[82] found that rTMS applied over the dorsolateral prefrontal cortex over 2 weeks improved depressive symptoms in over half of the patients with TRD.[82] As yet, rTMS does not appear to be as effective in elderly patients or in patients who have failed numerous pharmacologic therapies.
VNS involves implanting a generator in the patient's chest -- similar to a cardiac pacemaker -- to deliver intermittent-pulsed electrical signals to the left vagus nerve. Approved for adults with TRD and medication-resistant epilepsy, VNS alters brain activity without any known neuropsychologic impairments,[83] although it has been reported to trigger temporary and short-lived manic episodes. It is limited to patients who have failed to respond to at least 4 adequate trials of medication and/or ECT treatment regimens. Unlike other nonpharmacologic options that afford benefits in as short as 10 treatments, VNS provides a gradual improvement, possibly peaking at 24 months. It is recommended to be used in conjunction with other traditional therapies (pharmacologic and/or ECT) for optimal long-term benefits. Common side effects include a hoarse voice, difficulty swallowing, and cough. A recent meta-analysis of open studies on VNS for TRD has found significant symptom reduction in both the short and long term,[84] although a double-blind study was inconclusive.[85]
As with ECT, MST aims to induce a seizure through the magnetic stimulation of the cortex. While still in the investigational stages,[86] MST provides more targeted focal seizures than does ECT by inducing rapidly alternating intense magnetic fields. MST provides greater control of intracerebral current intensity than does ECT with seizures of shorter duration, resulting in fewer subjective side effects.[86] Deep brain stimulation (DBS) is another investigational treatment that requires the implantation of 2 electrodes bilaterally into the skull that are connected to a pacemaker implanted under the pectoralis muscles. The electrodes each have 4 active stimulation sites to provide continuous stimulation. This approach is the most focally targeted of these novel nonpharmacologic therapies.[87] It is hoped that DBS, if approved, might be an appropriate option for patients who have failed multiple pharmacologic trials.
Which psychotherapeutic approach has been shown to be effective for patients with MDD or TRD?
| Your Colleagues Responded: | |||
| Psychoanalytic therapy | 9% |
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| Rational emotive therapy | 4% |
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| Supportive psychotherapy | 21% |
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| CBT | Correct Answer | 64% |
Cognitive behavioral therapy has been shown to be as effective as drug therapy for MDD[88] and appears to have a synergistic effect when used in conjunction with pharmacotherapy for chronic MDD or TRD.[89] CBT enables patients to learn how their cognitive and behavioral patterns influence their interpersonal life -- and teaches patients how to change their maladaptive (or distorted) patterns of thought and behavior. As with other forms of psychotherapy, CBT is tolerated well with no known side effects. CBT is especially appropriate for patients who have failed an antidepressant. Outcomes associated with CBT are equivalent to those of another trial of a different agent.
In a multicenter study, 681 adult patients with chronic forms of nonpsychotic MDD were randomized to receive either nefazodone (maximum dose 600 mg/day) for 12 weeks, 16 to 20 sessions of cognitive behavioral therapy, or a combination of the 2 approaches.[89] The overall rate of response (remission and satisfactory response) was comparable for both monotherapies (48%); however, 73% of patients responded to the combination therapy (P < .001). Although all of the patients in the study had had active chronic depression for many years, 85% of those in the combination treatment group had a response to treatment by week 12 -- in comparison to only 55% in the nefazodone group and 52% in the psychotherapy group.[89]
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